PROJECT SUMMARY: The contributions of inflammation to ischemic cardiovascular disease has been well recognized. It is generally thought that monocyte/macrophage components of the innate immune system are central to the initiation and progression of atherosclerotic disease. Recent developments by others have suggested that there are specialized subsets of monocytic cells with particular functions and we have developed systems that can further assess heterogeneity within hematopoietic cells. Our plan is to use the emerging technologies that permit clonal assessments of heterogeneity to address the question of what specific subsets of monocyte/macrophages drive atherosclerosis. We will determine if monocyte/macrophages are born with endowed predisposition to atherogenesis or acquire such features after arrival at an atheroma. We will define molecular drivers of such functional attributes and test types of interventions targeting monocyte/macrophages to reduce the risk of progressive atherosclerosis.